Diagnosis and Treatment of Opioid Dependence Matthew A. Torrington, MD AAFP ASAM Medical Director, Matrix Institute Narcotic Treatment Program Clinical Research Physician, UCLA Integrated Substance Abuse Programs Medical Director, Prometa Center, Los Angeles

AAPainMed,APainS, ASAM defined ADDICTON in 2001 Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving Savage et al., 2001

DSM 4 criteria for drug abuse Significant impairment or distress resulting from use Failure to fulfill roles at work, home, or school Persistent use in physically hazardous situations Recurrent legal problems related to use Continued use despite interpersonal problems

DSM 4 criteria for drug Dependence ≥ 3 of the following occurring in the same 12- month period 1. Desire or unsuccessful efforts to cut down on use 2. Large amount of time spent obtaining drugs, using drugs, or recovering from drug effects 3. Social, occupational, or recreational activities reduced because of drug use 4. Drug use continued despite knowledge that a physical or psychological problem is being caused or exacerbated by use 5. Use of drug in larger amounts or for longer periods of time than originally anticipated

6. Tolerance Need for increased amounts of drugs to achieve desired effect; or Diminished effect with continued use of the same amount of drug Tolerance develops normally with repeated use of some drugs

7. Withdrawal withdrawal syndrome with cessation of use, reduction of use, or use of an antagonist Drugs or related substances taken to relieve or avoid withdrawal symptoms

Addiction is NOT: Physical dependence - characteristic withdrawal syndrome emerges upon decreased blood levels of substance or antagonist administration Tolerance - increasing amount of drug needed over time to induce the same effect Both are neuroadaptive states resulting from chronic drug administration

Pseudoaddiction operationally defined as aberrant drug-related behaviors that make patients with chronic pain look like addicts. these behaviors stop if opioid doses are increased and pain improves (Weissman and Haddox, 1989). This indicates that the aberrant drug-related behaviors were actually a search for relief Little data on the subject, but evidence in rats

Substance Dependence A Multifactorial Brain Disease Biological Dysregulation Social Cultural Substance Dependence Psychological Environmental In the United States, an estimated 22 million people suffer from substance dependence or abuse. The humanistic and societal impact of substance dependence is devastating as is the economic burden of the disease, estimated at over $345 billion annually. Substance dependence is a multifactorial disease, which includes psychosocial, environmental, biological, and genetic components. Scientific evidence demonstrates that the substance-dependent brain is physiologically and chemically different from a nondependent brain. Substance dependence susceptibility appears to be determined by biological, genetic, psychological, social, cultural, and environmental factors. Due to the complexity of addiction, a combination of pharmacologic and behavioral interventions offers the greatest likelihood of optimal patient outcomes. U.S. Department of Health and Human Services. Updating Estimates of the Economic Costs of Alcohol Abuse in the United States: Estimates, Update Methods, and Data. December 2000;1. Executive Office of the President, Office of National Drug Control Policy. The Economic Costs of Drug Abuse in the United States: 1992-1998. September 2001:3. World Health Organization. Neuroscience of Psychoactive Substance Use and Dependence. 2004. Genetic WHO. Neuroscience of Psychoactive Substance Use and Dependence. 2004.

Substance Dependence Is a Disease An interruption, cessation, or disorder of bodily function, system, or organ; When something is wrong with a bodily function.1 Determinants include environment and genetics (nature and nurture). Substance Dependence A disorder of the normal biological regulation of brain chemicals, specifically the GABA system in the brain. Determinants include environment and genetics 1. Stedman’s Medical Dictionary. Baltimore, Md: Williams & Wilkins; 2000.

Substance-related disorders Intoxication use of substance resulting in maladaptive behavior Withdrawal negative reactions that occur when use is discontinued or drastically reduced Delirium Dementia Psychosis Mood disorder Anxiety Sexual dysfunction Sleep disorder

Slide 11: The reward pathway Tell your audience that this is a view of the brain cut down the middle. An important part of the reward pathway is shown and the major structures are highlighted: the ventral tegmental area (VTA), the nucleus accumbens and the prefrontal cortex. The VTA is connected to both the nucleus accumbens and the prefrontal cortex via this pathway and it sends information to these structures via its neurons. The neurons of the VTA contain the neurotransmitter dopamine which is released in the nucleus accumbens and in the prefrontal cortex (point to each of these structures). Reiterate that this pathway is activated by a rewarding stimulus. [Note: the pathway shown here is not the only pathway activated by rewards, other structures are involved too, but only this part of the pathway is shown for simplicity.]

Slide 30: Summary; addictive drugs activate the reward system via increasing dopamine neurotransmission In this last slide, the reward pathway is shown along with several drugs that have addictive potential. Just as heroin (morphine) and cocaine activate the reward pathway in the VTA and nucleus accumbens, other drugs such as nicotine and alcohol activate this pathway as well, although sometimes indirectly (point to the globus pallidus, an area activated by alcohol that connects to the reward pathway). While each drug has a different mechanism of action, each drug increases the activity of the reward pathway by increasing dopamine transmission. Because of the way our brains are designed, and because these drugs activate this particular brain pathway for reward, they have the ability to be abused. Thus, addiction is truely a disease of the brain. As scientists learn more about this disease, they may help to find an effective treatment strategy for the recovering addict.

Slide 23: Addiction vs dependence As you have just explained, different parts of the brain are responsible for the addiction and dependence to heroin and opiates. Review the areas in the brain underlying the addiction to morphine (reward pathway) and those underlying the dependence to morphine (thalamus and brainstem). Thus, it is possible to be dependent on morphine, without being addicted to morphine. (Although, if one is addicted, they are most likely dependent as well.) This is especially true for people being treated chronically with morphine for pain, for example associated with terminal cancer. They may be dependent--if the drug is stopped, they suffer a withdrawal syndrome. But, they are not compulsive users of the morphine, and they are not addicted. Finally, people treated with morphine in the hospital for pain control after surgery are unlikely to become addicted; although they may feel some of the euphoria, the analgesic and sedating effects predominate. There is no compulsive use and the prescribed use is short-lived.

Opiates OxyContin Propoxyphene Hydrocodone Hydromorphone Meperidine long acting oral Propoxyphene (Darvon) Hydrocodone (Vicodin) Hydromorphone (Dilaudid) Meperidine (Demerol), Diphenoxylate (Lomotil) Codeine http://www.chemheritage.org/EducationalServices/pharm/asp/images/heroin.gif

Opiate Abuse Total number of drug mentions in drug abuse-related emergency department episodes, by type of drug, 1997-00       Cocaine Heroin Marijuana ------------------------------------------------------------------------         1997 161,083 70,712 64,720 1998 172,011 75,688 76,842 1999 168,751 82,192 87,068 2000 174,881 94,804 96,426 Source: U. S. Department of Health and Human Services, SAMHSA, Office of Applied Studies, Emergency Department Trends from the Drug Abuse Warning Network Preliminary Estimates January - June 2001 with Revised Estimates 1994-2000, February 2002. http://www.nrc.nl/W2/Lab/Profiel/Drugs/

Heroin Prevalence Across years and across cultures, prevalence of heroin abuse is fairly stable at about 1.5% of the adult population. Social upheaval linked to increases in heroin abuse (Afghanistan, Iraq, Russia)

                                 

Heroin Heroin is processed from morphine (diacetylmorphine) Morphine is a naturally occurring substance extracted from the seedpod of the Asian poppy plant. Heroin usually appears as a white or brown powder. Street names "smack," "H," “horse,” "skag," and "junk" "Mexican black tar,” “China White” Originally produced by Bayer as a “non addictive” analgesic www.thinkbigdesigns.com/ justin/Heroin.jpg

Opiate EFFECTS Desirable Undesirable Euphoria - heroin produces greater ‘rush’ than morphine due to  lipophilicity Prolonged sense of contentment and well-being Undesirable Nausea and vomiting Respiratory depression –  in sensitivity of respiratory centre to PCO2 Constipation -  tone +  motility in GI tract DON’T RX OPIATES WITHOUT CONSIDERING THIS Pupillary constriction - stimulation of oculomotor nucleus

MECHANISM OF ACTION Heroin metabolites act on  receptors on GABA neurons to uninhibit the firing of dopaminergic neurons in VTA. This results in  DE release in Nacc.

Slide 8: Dopamine neurotransmission and modulation by endogenous opiates Using the close-up of a synapse, continue using dopamine for your example of synaptic function. Explain that it is synthesized in the nerve terminal and packaged in vesicles. Reiterate the steps in neurotransmission. Show how the vesicle fuses with the membrane and releases dopamine. The dopamine molecules can then bind to a dopamine receptor (in pink). After the dopamine binds, it comes off the receptor and is removed from the synaptic cleft by uptake pumps (also proteins) that reside on the terminal (arrows show the direction of movement). This process is important because it ensures that not too much dopamine remains in the synaptic cleft at any one time. Also point out that there are neighboring neurons that release another compound called a neuromodulator. Neuromodulators help to enhance or inhibit neurotransmission that is controlled by neurotransmitters such as dopamine. In this case, the neuromodulator is an "endorphin" (in red). Endorphins bind to opiate receptors (in yellow) which can reside on the post-synaptic cell (shown here) or, in some cases, on the terminals of other neurons (this is not shown so it must be pointed out). The endorphins are destroyed by enzymes rather than removed by uptake pumps.

Slide 16: Morphine binding within the reward pathway Reiterate that morphine binds to receptors on neurons in the VTA and in the nucleus accumbens. This is shown here within the reward pathway. Indicate that you will show how morphine activates this pathway on the next slide.

Tolerance, Addiction, and Withdrawal With regular opiate use, tolerance develops. As higher doses are used over time, physical dependence develops. Withdrawal, which in regular abusers may occur as early as a few hours after the last administration drug craving, restlessness, muscle and bone pain, insomnia, diarrhea and vomiting, cold flashes with goose bumps ("cold turkey"), kicking movements ("kicking the habit"), etc. www.naplesnews.com/cgi-bin/ sendto.pl?location=specials

Opiate withdrawal Major withdrawal symptoms peak between 48 and 72 hours after the last dose Duration and intensity dependent on quantity and half live of opiates being used Heroin WD usually subsides after about a week. Methadone WD can last weeks RX OPIATES CAUSE WITHDRAWAL TOO http://www.heroinaddiction.com/Pictures/withdrawal.jpg

SYMPTOMS OF WITHDRAWAL Picture from: www.schoolscience.co.uk/.../4/ biology/medicines/drugs4.html

MOA Withdrawal On cessation of heroin excessive cAMP production occurs causing withdrawal symptoms

Opiate Overdose Treatment Respiratory depression, CNS depression, Myosis, signs of drug abuse, history R/O hypoglycemia, acidemia, fluid and electrolyte abnormalities Support: airway, ventilation, cardiac function, Naloxone HCL 0.4-0.8mg initially; repeat PRN

Treatment of opiate dependence Comprehensive treatment gives best chance of long lasting remission Opiate replacement or pharmacologic support of withdraw symptoms Cognitive Behavioral Treatment: matrix, counseling, etc. 12 step work CAN NOT RX OPIATES FOR OPIATE WD

Relapse curves for heroin, tobacco and alcohol addiction

Effect of Common Opiates at mu receptor Heroin, morphine, methadone Buprenorphine ? tramadol Naltrexone (Revia, Vixo) Nalmefene naloxone Full Agonist Partial Agonist Antagonist

Receptor Binding at Mu receptor Morphine like effect Weak morphine like effects with strong receptor affinity No effect in absence of an opiate or opiate dependence Agonist Opens door Partial Agonist Opens door with safety chain Antagonists Dummy key

Agonist Therapy Methadone is the gold standard Must be administered in setting of OTP, Opiate Treatment Program Highly regulated Can be used for pain Legislation prevents the use of agonists specifically for the treatment of opiate dependence outside the setting of OTP

THE DOSING WINDOW

How is methadone better than heroin? Legal Avoids needles Known amount ingested

Normal Range “Comfort Zone” Methadone Simulated 24 Hr. Dose/Response At steady-state in tolerant patient “Loaded” “High” “Abnormal Normality” Dose Response Normal Range “Comfort Zone” Subjective w/d “Sick” Objective w/d Time 0 hrs. 24 hrs. Opioid Agonist Treatment of Addiction - Payte - 1998

How is methadone better than heroin? Legal Avoids needles Known amount ingested Slow onset: no “rush” Long acting: can maintain “comfort” or normal brain function Stabilized physiology, hormones, tolerance

Four questions patients ask: How is methadone better for me than heroin? What is the right dose of methadone for me? How long should I stay on methadone? What are the side effects of methadone?

What is the right dose? Eliminate physical withdrawal Eliminate ‘craving’ Comfort/function: usually trough is 400-600 ng/ml, peak no more than twice the trough. Not over-sedated Blocking dose

Normal Range “Comfort Zone” Methadone Simulated 24 Hr. Dose/Response At steady-state in tolerant patient “Loaded” “High” “Abnormal Normality” Dose Response Normal Range “Comfort Zone” Subjective w/d trough “Sick” Objective w/d Time 0 hrs. 24 hrs. Opioid Agonist Treatment of Addiction - Payte - 1998

Ref: J. C. Ball, November 18, 1988 Slide adapted from Tom Payte

“How Much???? Enough!!!” Tom Payte, MD

Four questions patients ask: How is methadone better for me than heroin? What is the right dose of methadone for me? How long should I stay on methadone? What are the side effects of methadone?

Relapse to IV drug use after MMT 105 male patients who left treatment Percent IV Users Treatment Months Since Stopping Treatment Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991 Opioid Agonist Treatment of Addiction - Payte - 1998

“How Long??? Long Enough!!” Tom Payte, MD

Four questions patients ask: How is methadone better for me than heroin? What is the right dose of methadone for me? How long should I stay on methadone? What are the side effects of methadone?

Opiate effects, physical Predictable physical effects of administering opiates: Tolerance: the body becomes efficient in processing the drug and requires ever higher doses to produce the desired effect. Dependence: when the drug is discontinued there are typical withdrawal signs and symptoms.

Side effects of methadone: General opiate effects: Sedation/stimulation Maintained phys. dependence (stable) hypogonadism (not as severe as with heroin, may be dose dependent) Constipation Slight QTc prolongation on ECG (Martell etal) Sweating Methadone treatment tied to regulated clinic

Treatment Outcome Data 4-5 fold reduction in death rate reduction of drug use reduction of criminal activity engagement in socially productive roles reduced spread of HIV excellent retention (see: Joseph et al, 2000, Mt. Sinai J.Med., vol67, # 5, 6)

Crime among 491 patients before and during MMT at 6 programs Crime Days Per Year Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991 Opioid Agonist Treatment of Addiction - Payte - 1998

HIV CONVERSION IN TREATMENT HIV infection rates by baseline treatment status. In treatment (IT) n=138, not in treatment (OT) n=88 Source: Metzger, D. et. al. J of AIDS 6:1993. p.1052 Opioid Maintenance Pharmacotherapy - A Course for Clinicians - 1997

Buprenorphine

Buprenorphine for Opiate Dependence: Suppresses withdrawal Substitutes for street opiates Blocks subsequently administered opiates Safety in long term use

Buprenorphine pharmacology contd. “Less bounce to the ounce” Ceiling effect on respiratory depression Less physical dependence capacity Blunts effect of subsequently administered full agonists Precipitates withdrawal in moderate to severely dependent people

Buprenorphine: Clinical Pharmacology Tight Receptor Binding long duration of action slow onset mild abstinence long t 1/2 for tx of opiate dependence 37.5 hours shorter t 1/2 for analgesia 3-6 hours

Good Effect

Respiration

Intensity of abstinence Buprenorphine Morphine 60 50 40 30 20 10 Himmelsbach scores 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Days after drug withdrawal

Buprenorphine/Naloxone combo SUBOXONE 4 part buprenorphine: 1 part naloxone Sublingual: Opiate agonist effect from buprenorphine Intravenous: Opiate antagonist effect from naloxone

Addition of Naloxone Reduces Abuse Potential Naloxone will block buprenorphine’s effects by the IV but not the sublingual route Sublingual absorption of buprenorphine @ 70%; naloxone @ 10% If injected, BUP/NX will precipitate withdrawal in a moderately to severely dependent addict

A Sequential Pharmacological Intervention Model for Opiate Dependence Naltrexone Buprenorphine maint. Successful Medication-free Opiate Dependent Daily Buprenorphine Unsuccessful Methadone

Overview to the Drug Addiction Treatment Act of 2000 – An Amendment to the Controlled Substances Act (October, 2000)

Narcotic drug: Amended Controlled Substances Act Approved by the FDA for use in maintenance or detoxification treatment of opioid dependence Schedule III, IV, or V Drugs or combinations of drugs 1. Note that no medication is approved as of January, 2001.

Practitioner requirements: Amended Controlled Substances Act Practitioner requirements: “Qualifying physician” Has capacity to refer patients for appropriate counseling and ancillary services No more than 30 patients (individual or group practice) 1. The practitioner must be a “qualifying physician” (as defined in a moment), AND must have the capacity to refer patients for appropriate counseling and ancillary services, AND cannot treat more than 30 patients. 2. The limit on the number of patients that can be treated applies to both an individual physician (solo practice) and to group practices. For example, a group of six physicians can treat only 30 patients. It is possible for this restriction to change – the Secretary can create by regulation different limits for a group practice. However, this has not been done (as of January, 2001).

Amended Controlled Substances Act “Qualifying physician”: A licensed physician who meets one or more of the following: 1. Board certified in Addiction Psychiatry 2. Certified in Addiction Medicine by ASAM 3. Certified in Addiction Medicine by AOA 4. Investigator in buprenorphine clinical trials 1. A person can be a “qualifying physician” if he/she fulfills any one of seven criteria (which are continued on the next slide).

Amended Controlled Substances Act “Qualifying physician” (continued): Meets one or more of the following: 5. Has completed 8 hours training provided by ASAM, AAAP, AMA, AOA, APA (or other organizations which may be designated by HHS) 6. Training/experience as determined by state medical licensing board 7. Other criteria established through regulation by the Secretary of Health and Human Services 1. This curriculum has been designed to address the 8 hours of training designated as one of the criteria for becoming a “qualifying physician.”

Buprenorphine: Potent Analgesic 20-50 times potency of morphine Available worldwide for pain treatment Injectable formulation available in U.S. Usual analgesic dose: .2-.4 mg sl Higher dose for opiate dependence

Buprenorphine and Pain Animal data don’t predict human data Good potent analgesic Mild CVS effect, mild G-I effect Ceiling effect on respiratory depression Analgesia not compromised by ceiling. Effective for long term use mos. to yrs.

Buprenorphine: Analgesic Profile Rapid onset of action Long duration of peak effect (60-120 min) Long half life (3.5 hrs) Analgesic action up to 8 hrs. No apparent analgesic ceiling effect at doses below 300 mg Ms equivalent; no inverted U Ceiling effect on respiratory depression Low physical dependence profile

References Tomkins DN, Sellers EM (2001) Addiction and the brain: the role of neurotransmitters in the cause and treatment of drug dependence. Canadian Medical Association Journal 164 817-821 O’Connor P, Fiellin DA. (2000) Pharmacological Treatment of Heroin- Dependent Patients Annals of Internal Medicine 133 40-54 Sneader W. (1998)The Discovery of Heroin. Lancet 352 (9141) 1697- 1699 Rang HP, Dale MM, Ritter JM (1999). Pharmacology 4th ed. Edinburgh : Churchill Livingstone Wills S (1997) Drugs of abuse. London : Pharmaceutical Press Steve Shoptaw, Presentation, UCLA Addiction Clinic Course, 2005, with permission Judith Martin, Presentation, COMP Lecture, 2005 with permission